In our studies of stuttering, we have been working with a group of Pakistani stuttering families in which we have previously shown that a gene located on chromosome 12 is implicated in the cause of this disorder. We have enrolled several cohorts of subjects for case-control studies designed to identify the specific causative gene within this region on chromosome 12. These cohorts consist of 100 unrelated Pakistani stutterers and 100 population-matched controls, and 200 European unrelated cases and 100 normal controls. We performed an association study in these subject populations using 500 single nucleotide polymorphisms (SNPs) and identified several sub-regions of the interval on chromosome 12 that show evidence of being at higher frequency in the stuttering cases. We are currently evaluating two genes in this region, ASCL1 and STAB2 as candidates for the cause of this disorder. We have also continued our studies in a group of families in Cameroon, West Africa, in which stuttering occurs as a simple inherited trait. We have previously obtained evidence that a gene on chromosome 1 is responsible in the largest of these families, and we are currently working to narrow the chromosomal region and to evaluate candidate genes in this region. We have now identified 4 additional large families in Cameroon in which stuttering occurs as a simple inherited trait, and we are sampling these families for genetic linkage studies. [unreadable] [unreadable] Our studies of deficits in the sense of taste currently focus on sweet taste. During the past year, we have derived clones of all 21 different forms of the human T1R2 sweet taste receptor gene that exist in populations world wide, and cloned these into mammalian cell expression vectors for cell-based studies of sweet taste receptor function. While all receptors appear to be functional in ex vivo calcium release assays in transfected cells, some forms clearly posess different sensitivity to sweet agonists, and we are currently quantitating these differences. We are also testing human subjects for their sensitivity to a variety of sugars and artificial sweeteners, and obtaining DNA from these subjects to identify the forms of the sweet taste receptor gene they carry. The goal of these studies is to identify the genetic basis of differences in sweet taste perception between different individuals. We have made psychophysical measurements of sucrose sensitivity of 134 unrelated normal subjects, and shown that individuals are stable in the ability to detect this sugar, and that there is wide variation among individuals in the population. We have obtained DNA sequence information from the T1R2 and T1R3 genes (which together encode the major sweet receptor) in these subjects, and are currently looking to see if any of these DNA sequence variants correlate with sucrose sensitivity in these subjects. [unreadable] [unreadable] Our studies are on deficits in auditory pitch perception (tune deafness) are continuing. We have performed analysis of phonological (speech sound) processing in a group of 35 tune deaf subjects and compared this to a group of 34 subjects matched for age, gender, education, and handedness. We have found that tune deaf subjects have normal auditory and word memory, but have significant deficits in processing of phonemes. This suggests that the neural mechanisms involved in muscial perception overlap with those used for speech perception.